Recent evidence shows that neutrophils are capable of killing microorganisms in an extracellular location, in part by secreting antimicrobial peptides. This proposal explores the synthesis, function and structure of human cathelicidin (FALL-39/CAP18), an abundant protein of neutrophils and a likely component of an extracellular microbicidal system. The proposal hypothesizes that neutrophil elastase on the surface of the cells is the activating enzyme that specifically cleaves the secreted pro form of the molecule to its microbicidal form. The aims include: 1) characterization of the post translational processing of human cathelicidin; 2) characterization of the enzymes involved in the processing of procathelicidin to mature cathelicidin and identification of the site of their activity; 3) determination of the microbicidal activity of purified cathelicidins and determination of their contribution to the extracellular antimicrobial activity of human neutrophils; 4) exploration of the function of the conserved cathelicidin precursor (cathelin) in neutrophils as a carrier of neutrophil antimicrobial peptides; and 5) biosynthesis and purification of a representative procathelicidin in sufficient amounts and purity to determine its crystallographic structure. Thus the overall goal of the proposal is to define a recently recognized human host defense mechanism that may be important in resistance to microbial infection.